Patients suffering from uterine fibroids require intervention in order to improve the diseases' symptoms.
Uterine fibroids, which also called leiomyomata are common pelvic fibroid tumors occurring in up to 20% of women over 30 years of age. Leiomyomata represent one of the most frequent indications of surgical procedures in woman of reproductive age. Studies show that up to 77% of women have microscopic or macroscopic uterine fibroids at the time of menopause (Cramer et al, 1990). Leiomyomata may be 1 mm to 20 cm in diameter. Usually, treatment choice is guided by the patient's age and desire to preserve fertility and/or her uterus.
Most fibroids are asymptomatic but nearly half of women with fibroids have significant and often disabling symptoms including menorrhagia, pelvic pain, dysmenorrhea and pressure effects. In addition, fibroids that distort the uterine cavity can have adverse effects on fertility (American Society for Reproductive Medicine. Myomas and reproductive function. Fertil Steril 2008; 90:S125-S130 and Somigliana E, Vercellini P, Daguati R, et al. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update 2007; 13:465-76 and Kolankaya A, Arici A. Myomas and assisted reproductive technologies: when and how to act? Obstet Gynecol Clin North Am 2006; 33:145-52 and Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002; 17:1424-30.).
In such women, heavy uterine bleeding is a leading reason for medical consultation, surgery and work days lost (Collins J, Crosignani P G. Endometrial bleeding. Hum Reprod Update 2007; 13:421-31).
Over the last few years a variety of non-invasive treatments has become available to women with symptomatic fibroids and provides alternatives to the surgery.
Among others the use of anti-progestational agents before a surgical treatment has also been proposed to shrink uterine leiomoymata (WO2007/103510) or to render the patient amenorrheic. More specifically, WO2007/103510 relates to the treatment of uterine fibrosis using effective low doses of anti-progestational agent and length of treatment is shorter than previously thought possible.
A number selective progesterone receptor modulators (SPRMs) are under development for the treatment of gynecological diseases such as uterine fibroid, endometriosis, adenomyosis, abnormal uterine bleeding and dysfunctional uterine bleeding.
SPRMs such as ulipristal acetate (UPA) offer a unique potential clinical application in gynecology because effectively controls excessive bleeding, abdominal pain and size of myoma due to uterine fibroids and consequently improve the quality of life of the patients.
WO2008/083192 relates to formulations for improving the bioavailability of ulipristal acetate as one of the antiprogestins can be advantageously used inter alia to antagonize endogenous progesterone. Ulipristal acetate is cited as a possible antiprogestin among a large number of other relevant compounds. This patent application also provides a long list of disorders which might be treated by the claimed composition. Uterine fibroids is cited as one possible disease to cure among others. In the application use of UPA for the treatment of uterine fibroids is not explored explicitly and no examples are described in order to support the feasibility of treatment.
WO2009/095418 relates to a method for treating uterine fibroids, which method comprises administering to a patient in need thereof an effective amount of ulipristal acetate or any metabolite thereof. The inventors have shown that a low dosage, e.g. a daily dosage of 5 to 15 mg, preferably 10 mg, ulipristal acetate was the most effective. Ulipristal acetate or any metabolite thereof is particularly efficient to reduce or stop bleeding in a patient afflicted with uterine fibroids, or to reduce the size of uterine fibroids. The patient may be administered with an oral dosage of ulipristal acetate or any metabolite thereof during a period of about 2 to about 4 months.
In the prior art there was a strong technical prejudice against the long-term and repeated administration of SPRM's, for example asoprisnil, mifepristone or ulipristal acetate may induces progesterone-receptor modulator-associated endometial changes, which can be considered as harmful side effects (Mutter G. L., Mod. Path. (2008), 1-8; Nieman, L. K., Fertility and Sterility (2011) 95, 2, 767-772.)
Accordingly, UPA have been effective for the treatment of uterine fibroids, but the administration of UPA was limited to a period no longer than about 2 to about 4 months, preferably 3 months and widely accepted by skilled person.
Although treatments for about 2 to about 4 months exist, there remain significant unmet needs for improvement of uterine fibroid therapy.